FDA无菌原料药检查指南中英对照.docx

1、FDA无菌原料药检查指南中英对照GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERSFDA无菌原料药检查指南Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s). 注：本

2、文件是FDA现场检查官和其他FDA人员的参考资料。本文件并不束缚FDA，也不赋予任何人任何权利、特权、好处以便获得赦免。One of the more difficult processes to inspect and one which has presented considerable problems over the years is that of the manufacture of sterile bulk drug substances. Within the past several years, there have been a number of batches o

3、f sterile bulk drug substances from different manufacturers which exhibited microbiological contamination. One manufacturer had approximately 100 batches contaminated in a 6 month time period. Another had approximately 25 batches contaminated in a similar period. Other manufacturers have had recalls

4、 due to the lack of assurance of sterility. Although the Inspection Guide for Bulk Drug Substances provides some direction for the inspection of the sterile bulk drug substance, it does not provide the detailed direction needed.在过去多年中，现场检查最难的，也是出现问题最多的领域就是无菌原料药的制造。在过去几年中，有数批来自不同制造商的无菌原料药出现了微生物污染。一个制

5、造商在6个月中有100批产品有污染。另一个在相同的时间内出现了25批污染。其它一些供应商由于缺少无菌保证而召回了产品。虽然大宗原料药的现场检查指南在对无菌原料药的检查上提供了一些指导，但它未能提供所需要的详细指导。I. INTRODUCTION简介In the manufacture of the sterile bulk powders, it is important to recognize that there is no further processing of the finished sterile bulk powder to remove contaminants or i

6、mpurities such as particulates, endotoxins and degradants.在大宗无菌粉的制造中，认识到下面一点很重要，即最终无菌粉生产出来之后，再也没有别的程序来去除微粒、内毒素和降解物。As with other inspections, any rejected batches, along with the various reasons for rejection, should be identified early in the inspection to provide direction for the investigator. Fo

7、r example, lists of batches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. Because some of the actual sterile bulk operations may not be seen, and because of the complexity of the

8、 process, it is particularly important to review reports and summaries, such as validation studies, reject lists, Environmental Monitoring Summary Reports, QA Investigation Logs, etc. These systems and others are discussed in the Basic Inspection Guide. This is particularly important for the foreign

9、 sterile bulk drug substance manufacturer where time is limited. In the preparation for a sterile bulk drug substance inspection, a flow chart with the major processing steps should be obtained. Generally, the manufacture of a sterile bulk substance usually includes the following steps: 与其它检查一样，在检查的

10、早期，应向检查官提供拒绝使用的批（不合格批）及拒绝的各种理由，以使检查官把握方向。例如，应从制造商处获得一段时间内拒绝的批（不合格批）清单，为检查具体的工艺或系统提供方向。由于某些实际无菌操作可能看不见，同时，工艺复杂，审阅报告和概括，如验证研究，拒绝（不合格批）清单，环境检测概括，质量保证调查记录等。这些系统和相关部分在基本现场检查指南中有论述。这对海外无菌原料药制造商尤其重要，因为时间有限，在准备无菌原料药现场检查时，应获得包含主要工艺步骤的流程图。通常，无菌原料药的生产包含如下步骤：1. Conversion of the non-sterile drug substance to th

11、e sterile form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer).2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.3. Aseptic isolation of the sterile substance by centrifugatio

12、n or filtration.4. Aseptic drying, milling and blending of the sterile substance.5. Aseptic sampling and packaging the drug substance.1. 通过在溶媒中溶解，将有菌原料药转换为无菌原料药。通过无菌反应罐中的过滤和收集实现溶剂的灭菌。2. 在无菌反应罐中进行无菌原料药的无菌沉淀或结晶。3. 通过离心或过滤进行原料药的无菌离析。4. 无菌原料药的干燥，磨粉和混合。5.无菌抽样和包装。These operations should be performed in cl

13、osed systems, with minimal operator handling. Any aseptic operations performed by an operator(s) other than in a closed system should be identified and carefully reviewed.这些操作应在封闭系统进行，尽可能少的人工参与。如果在密封系统之外的操作员进行无菌操作，应当标示出来并仔细审查。II. COMPONENTS组成部分In addition to the impurity concerns for the manufacture

14、 of bulk drug substances, there is a concern with endotoxins in the manufacture of the sterile bulk drug substances. The validation report, which demonstrates the removal, if present, of endotoxins to acceptable levels, should be reviewed. Some manufacturers have commented that since an organic solv

15、ent is typically used for the conversion of the non-sterile bulk drug substance to the sterile bulk drug substance, that endotoxins will be reduced at this stage. As with any operation, this may or may not be correct. For example, in an inspection of a manufacturer who conducted extensive studies of

16、 the conversion (crystallization) of the non-sterile substance to the sterile drug substance, they found no change from the initial endotoxin level. Organic solvents were used in this conversion. Thus, it is important to review and assess this aspect of the validation report.除了担心无菌原料药的杂质之外，内毒素是无菌原料药

17、生产中的另一担心。应当审阅去除内毒素的验证报告。一些制造商认为，由于使用了有机溶媒来把有菌原料药转换为无菌原料药，内毒素在此阶段已经减少。如其它操作一样，这可能正确，也可能不正确。例如，在对进行了大量有菌转换为无菌试验的制造商的现场检查中，他们发现内毒素的含量没有变化。转换中使用了有机溶媒。因此，审阅和评估此方面的验证报告很重要。In the validation of this conversion (non-sterile to sterile) from an endotoxin perspective, challenge studies can be carried out on a

18、 laboratory or pilot scale to determine the efficiency of the step. Once it is established that the process will result in acceptable endotoxin levels, some monitoring of the production batches would be appropriate. As with any validation process, the purpose and efficiency of each step should be ev

19、aluated. For example, if the conversion (crystallization) from the non-sterile to the sterile substance is to reduce endotoxins by one log, then data should support this step.从内毒素角度来看该转换的验证(有菌到无菌)，重点应放在实验室或定点规模的研究来确定该步骤的有效性。一旦确定该工艺可以带来可接受的内毒素含量，只需监控批生产过程。如任何验证过程一样，每一步的目的和有效性均需证实。例如，如果一个记录显示有菌到无菌的转换（

20、结晶）减少了内毒素，那么，该数据应支持该步骤。Since endotoxins may not be uniformly distributed, it is also important to monitor the bioburden of the non-sterile substance(s) being sterilized. For example, gram negative contaminats in a non-sterile bulk drug substance prior to sterilization are of concern, particularly if

21、 the sterilization (filtration) and crystallization steps do not reduce the endotoxins to acceptable levels. Therefore, microbiological, as well as endotoxin data on the critical components and operational steps should be reviewed.由于内毒素可能不是均匀分布，因此，监控灭菌中的有菌原料药的生物负荷也很重要。例如，有菌原料药中的某些污染在灭菌前会很严重，特别是如果灭菌和

22、结晶过程不能减少内毒素含量。因此，应当审阅关键设备部分和操作环节的微生物和内毒素数据。III. FACILITY设施Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control. Because sterile bulk asepti

23、c facilities are usually larger, problems with pressure differentials and sanitization have been encountered. For example, a manufacturer was found to have the gowning area under greater pressure than the adjacent aseptic areas. The need to remove solvent vapors may also impact on area pressurizatio

24、n.无菌原料药的无菌加工设备的设计应与SVP无菌设备具有相同的设计特征。这包括温度、湿度和压力控制。由于无菌设备通常更大，压力不均和清洁问题常常遇到。例如，在现场检查中发现，一个制造商在更衣区域的压力比临近的加工区域的压力更大。过滤和结晶过程使用的压缩空气也可能影响着洁净区域的压力。Unnecessary equipment and/or equipment that cannot be adequately sanitized, such as wooden skids and forklift trucks, should be identified. Inquire about the

25、movement of large quantities of sterile drug substance and the location of pass-through areas between the sterile core and non-sterile areas. Observe these areas, review environmental monitoring results and sanitization procedures.不能充分清洗的非关键设备，如木刹车和叉车，应当标记。询问大量无菌原料药的流动和在有菌和无菌区域的穿行。观察这些区域，审阅环境监控结果和清洗

26、程序。The CGMP Regulations prohibit the use of asbestos filters in the final filtration of solutions. At present, it would be difficult for a manufacturer to justify the use of asbestos filters for filtration of air or solutions. Inquire about the use of asbestos filters.cGMP条例禁止在溶液的最终过滤时使用石棉过滤器。目前，制造商

27、很难找出使用石棉过滤器来过滤空气或溶液的理由，向FDA询问使用石棉过滤器的问题已无必要。Facilities used for the charge or addition of non-sterile components, such as the non-sterile drug substance, should be similar to those used for the compounding of parenteral solutions prior to sterilization. The concern is soluble extraneous contaminants

28、, including endotoxins, that may be carried through the process. Observe this area and review the environmental controls and specifications to determine the viable and non-viable particulate levels allowed in this area.用来运出或装入有菌成分的设备，如有菌原料药，应当与灭菌前生产注射制剂的设备相同。需要关注的是可溶解的外来污染物，包括内毒素，它们可能在生产过程传播。观察此领域，审

29、阅环境控制和参数，以确定可允许的活性和非活性微粒标准。IV. PROCESSING加工Sterile powders are usually produced by dissolving the non-sterile substance or reactants in an organic solvent and then filtering the solution through a sterilizing filter. After filtration, the sterile bulk material is separated from the solvent by crysta

30、llization or precipitation. Other methods include dissolution in an aqueous solution, filtration sterilization and separation by crystallization/filtration. Aqueous solutions can also be sterile filtered and spray dried or lyophilized.无菌粉通常通过在有机溶媒中溶解有菌物质或反应物以及在灭菌过滤器中的溶液过滤来生产。过滤后，无菌大宗材料通过结晶或沉淀被分离出来。其

31、它方法包括在水溶液中溶解，过滤灭菌和通过过滤或结晶离析。水溶液也可以是无菌过滤的，喷雾烘干或冻干。In the handling of aqueous solutions, prior to solvent evaporation (either by spray drying or lyophilization), check the adequacy of the system and controls to minimize endotoxin contamination. In some instances, piping systems for aqueous solutions h

32、ave been shown to be the source of endotoxin contamination in sterile powders. There should be a print available of the piping system. Trace the actual piping, compare it with the print and assure that there are no dead legs in the system.在水溶液的处理中，在溶液挥发前（喷雾烘干或冻干），检查系统的充足性和对减少内毒素污染的控制。在某些情况下，运送水溶液的管线

33、被发现是无菌粉中内毒素污染的来源。应当有管线系统的照片。跟踪实际的使用，与照片比较，保证系统中没有“死角”。The validation data for the filtration (sterilization) process should also be reviewed. Determine the firms criteria for selection of the filter and the frequency of changing filters. Determine if the firm knows the bioburden and examine their procedure